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Selectivity in multiple multicomponent reactions:types and synthetic applicationsOuldouz Ghashghaei1, Francesca Seghetti2 and Rodolfo Lavilla*1

Review Open Access

Address:1Laboratory of Medicinal Chemistry, Faculty of Pharmacy and FoodSciences and Institute of Biomedicine (IBUB), University of Barcelona,Av. de Joan XXIII, 27-31, 08028 Barcelona, Spain and 2Departmentof Pharmacy and Biotechnology (FaBiT), University of Bologna, ViaBelmeloro, 6, 40126, Bologna, Italy

Email:Rodolfo Lavilla* - rlavilla@ub.edu

* Corresponding author

Keywords:isocyanides; multicomponent reactions; reaction discovery; selectivity

Beilstein J. Org. Chem. 2019, 15, 521–534.doi:10.3762/bjoc.15.46

Received: 13 December 2018Accepted: 07 February 2019Published: 21 February 2019

This article is part of the thematic issue "Multicomponent reactions III".

Guest Editor: T. J. J. Müller

© 2019 Ghashghaei et al.; licensee Beilstein-Institut.License and terms: see end of document.

AbstractMultiple multicomponent reactions reach an unparalleled level of connectivity, leading to highly complex adducts. Usually, only

one type of transformation involving the same set of reactants takes place. However, in some occasions this is not the case. Selec-

tivity issues then arise, and different scenarios are analyzed. The structural pattern of the reactants, the reaction design and the ex-

perimental conditions are the critical factors dictating selectivity in these processes.

521

IntroductionOrganic synthesis has become fundamental in science and tech-

nology, affecting many aspects of our lives. Therefore, there is

a big need for the optimized preparation of a variety of com-

pounds [1-3]. In this context, multicomponent reactions

(MCRs) hold a privileged position, allowing the formation of

many bonds and connecting three or more reactants in one step

[4]. A particularly attractive and synthetically productive set of

MCRs involve di/polyfunctionalized substrates that can, conse-

quently, lead to repeated processes. The so-called multiple

multicomponent reactions (MMCRs) display impressive power

regarding connectivity and bond-forming efficiency and can be

considered as ideal synthetic processes in many aspects [5].

These features may be maximized if the controlled incorpora-

tion of distinct reactant units, belonging to the same class, along

the transformation would be feasible (Scheme 1). This review,

which does not intend to be exhaustive, deals with the selec-

tivity levels found in the literature and their impact on the syn-

thetic outcome. In this way we may find different scenarios:

i) completely unselective combinations leading to mixtures,

symmetrical adducts or polymers; ii) structurally preorganized

systems allowing the generation of macrocycles and iii) selec-

tive processes in which a determined combination arises in a

sequential manner, either directly or indirectly, through func-

tional group deprotection/generation. Stereoselectivity (where

Beilstein J. Org. Chem. 2019, 15, 521–534.

522

Scheme 1: Selectivity levels found in multiple multicomponent reactions. I) Innate selectivity; II) sequential selectivity; III) use of biased substrates;IV) use of protecting groups; V) generation of new functional groups; VI) polymerization; VII) macrocyclization; FG = functional group.

Scheme 2: Indiscriminate double Ugi MCR upon pyridine-2,6-dicarboxylic acid.

applicable) arising out of the individual MCRs or in the final

adduct, is not contemplated. Only the connectivity issues related

with the identity of the reactants are taken into account.

ReviewSubstrates displaying two (or more) identical functional groups

(FGs) have been reacted in a variety of MCRs. An early exam-

ple involves the synthesis of protease inhibitors by double Ugi

4CR using pyridine-2,6-dicarboxylic acid, isocyanides, amines

and aldehydes (Scheme 2), and the combinatorial implications

of this protocol were analyzed [6]. Ugi and Dömling soon real-

ized the potential of such experiments, which helped to pave the

way of combinatorial chemistry and its applications for the fast

generation of pharmacological hits through library deconvolu-

tion. The reactivity of the system led to complex product mix-

tures, with no practical substrate selectivity.

However, if in analogous experiments several reactants of a

kind, displaying different reactivities, are used, their relative

nucleophilicities/electrophilicities [7] may lead, in principle, to

biased mixtures. At the same time, this innate selectivity is not

straightforward, as the most reactive combination would

promote a fast first MCR, and likely the following MCR pro-

cesses may also involve this same set [8]. Experimental find-

ings showing complex mixtures, although far from statistical

product ratios, are the usual outcome of MMCRs involving

several reactants of one kind.

There are, however, cases where this indiscriminate reactivity is

synthetically useful: MCR polymerizations, typically involving

two doubly functionalized reactants, which yield macromolecu-

lar adducts [9-11]. In these processes, the reactivity of the

equivalent FGs is nearly identical in the reactants and in the

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Scheme 3: Representative examples of MCR-polymer synthesis. A) Biginelli HTS of polymers; B) Passerini;- C) Ugi-; D) metal-catalyzed MCR poly-merizations; E) alkyne-sulfonylazide-alcohol interactions; F) sulfur-amine-isocyanide combination.

oligo/polymeric intermediates, as they are usually connected

through long linear alkyl chains. Representative examples

include polymerizations using Biginelli [12], Passerini [13], Ugi

[14], metal-catalyzed MCRs [15], and reactive combinations in-

volving an alkyne-sulfonyl azide nucleophile [16] and sulfur,

amines and isocyanides [17] (Scheme 3).

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Scheme 4: Concept of multicomponent macrocyclization.

An interesting case, where this principle does not apply, is

introduced by Wessjohann [5,18], who introduced a family of

MMCRs leading to complex macrocyclic structures instead of

linear polymer chains. In these examples, a low concentration

together with the use of specific substrates tune the reactivity

pattern, promoting intramolecular interactions over intermolec-

ular polymerizations. Thus, the use of the right conditions and

the intelligent choice of the polyfunctionalized building blocks,

enable an “architectural approach” towards the MMCR synthe-

sis of macrocyclic adducts [19].

This multiple multicomponent macrocyclization strategy

[18,20] (Scheme 4) constitutes a breakthrough in the field, pro-

viding a powerful synthetic tool to systematically design and

prepare a variety of structures. The implementation of this ap-

proach goes beyond simple macrocycles, and was exploited to

deliver macromulticycles [21], supramolecular structures

(cryptands, cages, cryptophanes, podands, etc.) [22-24], cyclic/

macrocyclic peptides [25] and other complex structures in a

straightforward manner (Scheme 5). The diversity in these

systems arises not only from combining a variety of building

blocks (from simple aromatic and aliphatic substrates to

peptides, steroids, sugars, etc.) [26], but also from the different

MCRs used. Although the Ugi 4CR is the most commonly used

transformation in this context, interesting examples exploiting

other MCRs have been reported (Scheme 6) [27,28].

However, when the first MCR step in the process leads to a less

reactive intermediate, the system may stop temporarily at this

level, and once completed, a second MCR with a distinct set of

reagents may take place under more vigorous activation. This

allows for selective sequential MMCRs, although there is a

clear dependency on the structural features of a given substrate.

For instance, all known examples deal with ditopic compounds,

where the two reactive FGs are conjugated. In this way, after

the initial MCR, the intermediate adduct is somewhat deacti-

vated with respect to the initial substrate, and the remaining FG

is less prone to suffer the same transformation. Relevant exam-

ples are shown in Scheme 7.

Terephthalaldehyde is capable of undergoing sequential MCRs

in a selective manner with two different sets of reactants. In this

way, a variety of transformations involving Groebke–Black-

burn–Bienaymé (GBB)/Hantzsch, and Biginelli/Ugi-azide

sequential reactions were reported by Shahrisa [29]. Similarly,

Sharma and co-workers disclosed a related approach [30].

Moreover, 2,4-diaminopyrimidine underwent selective GBB

processes leading to a single monoadduct, which reacted again

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Scheme 5: Supramolecular structures out of MMCR macrocyclizations.

with another isocyanide/aldehyde pair to yield a 5-component

adduct in a selective manner. Interestingly, the protocol allows

control of the respective localization of all reactant inputs.

Thus, inverting the order of the MCRs leads to the complemen-

tary disposition of the residues in the final MCR adduct [31].

Non-symmetrically polyfunctionalized components can signifi-

cantly diversify the synthetic output of MMCRs. However, a

limiting factor in the design of MMCRs with such components

is the risk of generating undesired cross-adducts. This problem

can be avoided by introduction of protecting groups or through

the sequential generation of repeating FGs (see below). An al-

ternative strategy is to include those duplicated FGs displaying

distinct reactivity. In this way, one FG selectively reacts

through the first MCR, while its counterpart remains intact to be

exploited in a subsequent transformation.

This elegant concept has been reported by Orru [32], exploiting

a non-symmetrical diisocyanide A (Scheme 8). The designed

sequence requires the α-acidic isocyanide to undergo the 3CR

leading to a 2-imidazoline in the first step, the aliphatic

isocyanide remaining intact (without protection) and being later

incorporated in a variety of isocyanide-based MCRs. In this

way, the selective formation of intermediate B, leads to the

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Scheme 6: Macrocyclization by MMCRs. A) Staudinger MCR; B) boronic-imine MCR.

following MCR processes based in different isocyanide MCRs.

This approach made possible a remarkable 8-CR process for the

one-pot synthesis of compounds with up to 11 diversity points.

A conceptually distinct approach for selective MMCRs is based

in reactivity features. The Union concept (the combination of

MCRs) [33,34] is extremely fruitful and was developed by Ugi

and Dömling to perform a 7CR out of the combination of

Asinger and Ugi transformations (Scheme 9A) [35]. In this

context, chemoselectivity can be achieved when the key poly-

functionalized reactants bear the adequate FGs and the combi-

nation of MCRs becomes feasible. This can happen either by

the orthogonal reactivity of the participating FGs or because the

sequential character of the process implies the participation of

the first MCR adduct as a reactant in the following transformat-

ion. Several examples use this approach with the same set of

reagents leading to MMCRs, with limited structural variability

(Scheme 9B and C) [36,37]. However, in some occasions the

two processes are split up and higher levels of diversity can be

achieved.

In these cases, the consecutive reactions lead to adducts

displaying a diversity of substituents at several positions, which,

in principle, can be located at will, in a controlled manner. For

instance, the combination of a Petasis 3CR with an Ugi 4CR led

to a peptide structure with six diversity points arising directly

from the reactants (Scheme 10A) [38]. Similarly, a suitably

substituted aldehyde participates in a GBB MCR to yield an

adduct which participated in standard Ugi–Passerini processes

through the carboxylic acid functional group, untouched in the

first MCR (Scheme 10B) [39]. Furthermore, Reissert or Reis-

sert/Ugi reactions can be linked with Povarov MCRs through

the intermediacy of the enamine-containing adducts from the

former processes (Scheme 10C) [40].

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Scheme 7: Selective Sequential MMCRs. A and B) MCRs involving terephthalaldehyde; C) Multiple GBB processes with diaminodiazines.

Many additional combinations arise from the Union concept,

such as Bredereck–Passerini [41], pyridone-cyclocondensation/

Passerini–Ugi [42], azadiene-keteneimine Diels–Alder [43],

Asinger–Ugi [44], etc.

Another class of reactions highlight the importance of the

distinct kinetic reactivity of similar FGs present in the reactants

and in the initial adducts of the first transformation, then

enabling productive and selective combinations of the MCRs.

The synthesis of aminomethyltetrazoles arising from two

consecutive isocyanide-MCRs shows excellent selectivity and

broad scope, and although it combines two different transfor-

mations, the amine component (ammonia in the starting mix-

ture and a primary amino group in the first adduct) reacts at dif-

ferent rates in each substrate, allowing the controlled perfor-

mance of both processes, leading to a formal two-step 6CR [45]

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Scheme 8: Biased substrates for selective MMCRs.

Scheme 9: The Union concept. A) Asinger–Ugi combination; B) Passerini–Ugi/azide from anthranilic acid; C) Passerini–Ugi multiple MCR fromglutamic acid.

(Scheme 11A). Analogously, Ruijter reported an interrupted

Ugi process [46] involving a 2-(3-indolyl)ethyl isocyanide, an

aldehyde and an amine which elegantly led to the iminospiro

adduct C (Scheme 11B). This compound does not react under

the initial reaction conditions, but can be forced to do so in a

Joullié MCR with a new isocyanide/carboxylic acid pair [47].

Incidentally, this last process is also remarkably stereoselective,

something very unusual in Ugi-type reactions.

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Scheme 10: Relevant examples of consecutive MCRs exploiting the Union Concept. A) Petasis-Ugi combination; B) GBB-Ugi/Passerini combination;C) Reissert MCRs linked to a Povarov reaction.

Scheme 11: Selective MMCRs featuring FGs with distinct reactivity along the sequence. A) Synthesis of aminomethyltetrazoles by consecutiveisocyanide MCRs. B) Interrupted Ugi/Joullié sequence.

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Scheme 12: High order MMCRs. A) Ugi/Ugi–Smiles 7C combination; B) imidazoline-N-cyanomethylamide-Ugi union leading to an 8CR.

Finally, to exemplify the complexity levels that can be achieved

with this approach, we list two multiple MCRs showing their

power to reach very elaborate scaffolds with several diversity

points in short sequences. Westermann described a remarkable

Ugi/Ugi–Smiles protocol using a carboxylic acid provided with

a phenol group, which led to a 7-component transformation in a

sequential manner (Scheme 12A) [48]. The process can be

kinetically justified taking into account that the Ugi MCR with

the acid input is much faster than the Ugi–Smiles transformat-

ion involving the phenol. In another impressive transformation,

a formal 8-component adduct can be assembled through a

one-pot protocol combining imidazoline, cyanomethylamide

and Ugi MCRs. Although the final product is a complex

stereoisomeric mixture, the process stands as a milestone for the

rapid construction of complex structures, amenable to combina-

torial diversification (Scheme 12B) [32]. Incidentally, the reac-

tivity of the diisocyanide leading to the cyanomethylamide

MCR, features a distinct reactivity between the two FGs (see

above).

Another scenario involves substrates with different FGs where

the selective combination of consecutive MCRs can be carried

out by temporarily blocking one of the reactive sites along the

process. This sequential approach involves protection/deprotec-

tion steps in which one of the building blocks contains a pro-

tected FG to be subsequently (and selectively) activated for the

following MCRs.

For instance, the examples shown in Scheme 13 illustrate a

repetitive Ugi 4CR-deprotection-Ugi 4CR protocol to obtain

peptide nucleic acid (PNA) oligomers (Scheme 13A) [49],

peptidic tetrazoles and hydantoinimides (Scheme 13B) [50], re-

spectively. Incidentally, the later processes take place in solid

phase, which enhances their synthetic suitability.

The same strategy was exploited by Wessjohann for the synthe-

sis of RGD (Arg-Gly-Asp)cyclopeptoids [51]. In this case, they

developed a stepwise protocol in which two Ugi 4CRs, flanking

a deprotection, provided linear peptidic adducts. Afterwards,

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Scheme 13: Consecutive Ugi 4CR-deprotection–Ugi 4CR strategy towards A) PNA oligomers and B) peptidic tetrazoles and hydantionimides.

Scheme 14: Sequential Ugi 4CR-deprotection access to cyclopeptoids.

these intermediates were again deprotected and a final Ugi

4CR-macrocyclization efficiently afforded the final target

(Scheme 14).

Furthermore, additional sequential versions of multiple MCRs

have been employed to construct natural products. For instance,

Ugi reported the synthesis of a 6-aminopenicillanic acid deriva-

tive using two different MCRs [33,52]. As shown in

Scheme 15, the initial Asinger 4CR yielded an adduct which

was selectively deprotected for the following intramolecular

Joullié reaction, leading to the penam derivative.

Finally, an elegant MCR–deprotection strategy was reported by

Wessjohann for the synthesis of Tubugis, highly potent anti-

tumor peptidomimetics (Scheme 16) [53]. The convergent ap-

proach employs three different isocyanide-MCRs, efficiently

prepares the building blocks and combines them, intercalating

protecting group cleavages.

ConclusionThe MMCRs approach represents the most efficient way to

build chemical complexity and structural diversity around

meaningful scaffolds. When different sets of reactants are

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Scheme 15: Stepwise access to 6-aminopenicillanic acid derivative through an Asinger, deprotection, Joullié approach.

Scheme 16: A triple MCR-deprotection approach affording anticancer peptidomimetics.

involved in these processes, the control of the selectivity

becomes a fundamental issue. In this respect, a variety of

scenarios can be considered. Innate selectivity (the spontaneous

selection of reactants) is unknown and, arguably, it would be

difficult to reach under standard conditions. However, this lack

of selectivity allows the generation of complex mixtures of

adducts, useful in combinatorial chemistry for biological

purposes. On the other hand, MCR polymerization takes advan-

tage of this behaviour, and a variety of transformations lead to

well-defined macromolecules. An interesting case is found in

systems where the reaction conditions and the preorganization

of some inputs leads to selective macrocyclization, affording

extremely complex MCR adducts in just one step. Rationaliza-

tion of these processes allows programmed access to a variety

of structural types. On the contrary, when di(poly)functionali-

zed substrates display conjugation between the reactive FGs,

selectivity may arise. When the initial MCR adduct is less reac-

tive than the starting material, a sequential procedure may lead

to the following transformation with different reactants to afford

the final adducts in a selective manner. Alternatively, sub-

strates with two chemically distinct FGs of the same kind (i.e.,

isocyanides) may react at different rates, prompting selectivity,

usually in a sequential manner. Moreover, the generation of

novel FGs in the course of a given MCR can trigger a new one,

then allowing for selectivity in another sequential approach.

Finally, the use of protecting groups in reactants undergoing

MCRs leads to multistep transformations which, after suitable

deprotections, selectively afford the final adducts. Active

research is pursued in the field, aiming at the generalization of

the aforementioned concepts and their extension to diverse syn-

thetic outcomes.

AcknowledgementsFinancial support from the Ministerio de Economía y Competi-

tividad-Spain (MINECO, CTQ2015-67870-P) and Generalitat

de Catalunya (2017 SGR 1439) is gratefully acknowledged.

ORCID® iDsOuldouz Ghashghaei - https://orcid.org/0000-0002-5524-3697Francesca Seghetti - https://orcid.org/0000-0003-0478-7341Rodolfo Lavilla - https://orcid.org/0000-0002-5006-9917

Beilstein J. Org. Chem. 2019, 15, 521–534.

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